Ketamine or dextromethorphan formulations and methods of use

ABSTRACT

The present invention provides a method of treating depression disease in a treatment resistant patient comprising administering to a mucosal membrane of a patient an effective amount of a pharmaceutically acceptable composition comprising an effective amount of ketamine or dextromethorphan, wherein the mucosal administration of the ketamine or dextromethorphan containing composition allows for the mucosal absorption of the composition eliminating the digestive tract of the patient for effecting a rapid acting antidepressant treatment of the treatment resistant patient. This method includes administering the composition to a patient&#39;s mucosal membrane of a respiratory tract, a genitourinary tract, an oral tract, or rectal tract of the patient. A pharmaceutically acceptable composition comprising ketamine or dextromethorphan and a vehicle is disclosed. A biomarker for identifying a depressive disease is set forth.

CROSS-REFERENCE TO RELATED APPLICATION

This utility patent application claims the benefit of co-pending U.S.patent application Ser. No. 14/644,608, filed on Mar. 11, 2015, whichclaims the benefit of U.S. Provisional Patent Application Ser. No.62/005,326, filed on May 30, 2014, now expired. The entire contents ofU.S. patent application Ser. No. 14/644,608 and U.S. Provisional PatentApplication Ser. No. 62/005,326 are incorporated by reference into thisutility patent application as if fully written herein.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention provides for the mucosal, and preferably buccalformulations of compositions containing ketamine or dextromethorphan andmethods of administering mucosal and buccal formulations of compositionscontaining ketamine or dextromethorphan for treatment of unipolar andbipolar depression and depression disease that is resistant totreatment.

2. Description of the Background Art

Depression affects about 20% of the population and it is the leadingcause of disability in the U.S. Current treatments for depression areinadequate. It takes several weeks of treatment before beneficialeffects are observed, and about 30% of individuals still do not respond.There is thus a pressing need to identify effective and fast actingtherapeutic options for individuals suffering from depression.Accumulating evidence indicates that the anesthetic ketamine can producerapid antidepressant effects that last for up to two weeks. Use of thisoption, however, is severely limited because intravenous administrationof ketamine must be done in an inpatient setting, and is accompanied bynotable side effects. The identification of a fast acting antidepressantdrug that can be used in a general clinical population would represent atransformative advance in psychiatry.

Depression affects about 20% of Americans. It now begins earlier in lifethan in past decades, and rates are increasing. Individuals withdepression have a higher risk for a variety of health problems includingsubstance abuse, eating disorders, heart disease, and stroke. It is theleading cause of disability in the U.S., costing approximately $44billion in loss of productivity in a given year. Despite advances inantidepressant therapy, it still takes four to six weeks before approvedmedications are effective which results in significant morbidity.Further, about 30% of patients do not respond to treatment. Given thatdepression is one of the most common and costly brain diseases, there isan urgent need to develop more effective medications to treat thisdevastating disorder. Historical antidepressant drugs: Antidepressantdrugs were discovered serendipitously in the 1950s, with the repurposingof a monoamine oxidase inhibitor (iproniazid) and tricyclic (imipramine)that were originally approved for other indications. The introduction ofselective serotonin reuptake inhibitors (SSRIs) followed in the late1980s, which greatly improved the side effect profile of antidepressanttherapy, but did not provide significant advances in terms of efficacyor onset of action. These limitations are concerning because drugs thatare the mainstay of antidepressant pharmacotherapy have a delayed onsetof action (2-4 weeks) during which time patients are at high risk forsuicide. Fast acting antidepressant drugs: A major breakthrough in thetreatment of depression came in 2000 with ketamine reported as a fastacting antidepressant drug. Ketamine is a noncompetitive NMDA glutamatereceptor antagonist that has been used as an intravenous anestheticagent for several decades and has been shown to have rapid actingantidepressant effects in as fast as two hours in sub-anesthetic doses.Intravenous ketamine is almost exclusively used in the inpatient settingand is known for serious adverse effects such as hallucinations andsedation, but the widespread use of ketamine remains limited by its sideeffect profile which includes perceptual disturbances, confusion, and ashort lived “high”. The present invention provides a long felt andunresolved and unmet need for clinical methods and transbuccalformulations of ketamine or dextromethorphan for treating depression inpatients.

SUMMARY OF THE INVENTION

The present method provides a method of treating depressive disease(depression) in a patient comprising administering to a mucosal membraneof a patient an effective amount of a composition comprising aneffective amount of ketamine or dextromethorphan, or both ketamine anddextromethorphan, wherein said mucosal administration of saidcomposition allows for the transmucosal absorption of the compositioninto the patient's blood stream thereby eliminating the digestive tractof said patient for providing a rapid acting antidepressant effect fortreating depression in the patient. Preferably, this method of includesadministering said composition to said mucosal membrane of said patientover a time period from one millisecond to ten minutes, and morepreferably this method includes wherein the time period ofadministration ranges from one second to three minutes. This methodincludes wherein said composition is contained within a dosage formcapable of being administered to the mucosa of said patient or to themucosal membrane of said patient. Preferably, this method includeswherein said dosage form is a liquid, gel, powder. More preferably, thismethod includes wherein said dosage form is in the form of apharmaceutically acceptable troche, film, capsule, tablet, particle,solution, suspension, lollipop, lozenge, emulsion, spray, or aerosol.More preferably, this method includes wherein said effective amount ofsaid ketamine is 0.5 mg per kilogram of a patient's body mass. In a mostpreferred embodiment of this invention, the method, as described herein,includes administering said composition to said mucosal membrane that isin an oral cavity of said patient. The oral cavity is preferably thebuccal cavity of the patient. The methods of this invention includewherein the depression is selected from the group of unipolar depressiondisease, bipolar depression disease, and depression treatment resistantdisease.

Another embodiment of this invention provides a pharmaceuticallyacceptable composition comprising an effective amount of ketamine ordextromethorphan, or both ketamine and dextromethorphan, wherein saidketamine or said dextromethorphan is distributed within apharmaceutically acceptable vehicle, wherein said vehicle is capable ofbeing placed in contact with a mucosal membrane of a patient. Thecomposition and said vehicle are capable of delivery to an oral cavityof said patient, and more preferably are capable of delivery to a buccalcavity of the oral cavity of said patient. The pharmaceuticallyacceptable composition of this invention includes a dosage form that isa liquid, gel, or powder. Further, the pharmaceutically acceptablecomposition has a dosage form of a pharmaceutically acceptable troche,film, capsule, tablet, particle, solution, suspension, lollipop,lozenge, emulsion, spray, or aerosol. Preferably, the effective amountof said ketamine in said composition is 0.5 mg per kilogram of apatient's body mass.

In another embodiment of this invention, a pharmaceutically acceptablecomposition is provided comprising an effective amount of ketamine ordextromethorphan, or both ketamine and dextromethorphan, wherein saidketamine or said dextromethorphan is distributed within apharmaceutically acceptable vehicle, wherein said vehicle is capable ofbeing placed in contact with a mucosal membrane of a patient. Thecomposition and said vehicle are capable of delivery to an oral cavityof said patient, and more preferably are capable of delivery to a buccalcavity of the oral cavity of said patient, and wherein thepharmaceutically acceptable vehicle is a device having a mucoadhesivelayer containing said ketamine buffered to a pH of between about 4.0 and7.0, and a non-adhesive backing layer buffered to a pH of between 4.0and 6.0 wherein the pH of the mucoadhesive layer and the pH of thenon-adhesive backing layer are different, wherein the mucoadhesive layerand the non-adhesive backing layer comprise different combinations ofpolymers but each layer comprises at least one water-erodible polymerselected from the group of cellulosic polymers, olefinic polymers,polyethers, and polyalcohols. The water-erodible polymer is at least oneselected from the group consisting of polyacrylic acid, sodiumcarboxymethylcellulose, hydroxyethyl cellulose, hydroxyethylmethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylalcohol, polyethylene glycol, polyethylene oxide, and ethyleneoxide-propylene oxide co-polymers. Preferably, the pharmaceuticallyacceptable composition having the device that is in the form of atransmucosal buccal tablet or buccal film. The pharmaceuticallyacceptable composition includes at least one buffering agent containedin said mucoadhesive layer for use in buffering the pH of ketamine ordextromethorphan, or both ketamine and dextromethorphan. Optionally, thepharmaceutically acceptable composition includes a hydrophobic polymerfor coating said non-adhesive backing layer for controlling theerodibility of the layer

Another embodiment of this invention includes a biomarker foridentifying depressive disease in a patient comprising predictingresponsiveness to treating a patient by administration to said patientof a pharmaceutically acceptable composition of ketamine, ordextromethorphan, or a combination of ketamine and dextromethorphan, andevaluating a change in alterations in acoustic vocal parameterscomprising speech rate and voice frequency, and alterations incorticospinal excitability comprising resting motor threshold, in apatient at baseline prior to treatment and after treatment of saidpatient.

In another embodiment of this invention, a method of treating depressiondisease in a patient comprising administering to a patient an effectiveamount of a composition comprising an effective amount ofdextromethorphan via the oral route of the patient for providing a rapidacting antidepressant effect for treating depression in the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of the method of the present inventionproviding off-label use of a transbuccal ketamine formulation (i.e. acomposition capable of delivering ketamine to a buccal cavity of apatient) for rapid acting treatment of depression disease.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “patient” means any member of the animalkingdom, including but not limited to human beings, and animals.

As used herein, the term “buccal” is defined as “of, relating to,adjacent to, or in the direction of the cheek” of the oral cavity of apatient. The term “buccal cavity” is defined as “the portion of the oralcavity of a patient bounded by the lips, cheeks, and gums”. The term“buccal” is anatomically distinct from the “sublingual” region of theoral cavity. The term “sublingual” is defined as “below, or beneath thetongue”.

As used herein, the term “mucosal” is defined as “a membrane for liningall body passages that communicate with the exterior, such as forexample but not limited to the respiratory, genitourinary, oral, andrectal tracts of a patient's anatomy. The term “transmucosal” includes,for example, but not limited to administering a composition to themucosal membrane of a patient including wherein the composition iscapable of being held in contact with or in juxtaposition to mucosalmembrane of a patient or applied to the mucosal membrane of a patient,and wherein said composition is permitted to be absorbed/adsorbed by orinto the mucosal membrane of the patient.

As used herein, the term “effective amount” is defined as that amount ofa substance, a drug, or a composition that is capable of bringing abouta desired effect, such as for example, but not limited to, that amountof a substance, a drug, or a composition needed to treat a patient withdepressive disease.

We test two strategies for achieving fast acting antidepressant effectswith a much reduced side effect profile from existing options using anopen-label, cross-over design: 1) transbuccal dosing of ketamine, and 2)oral administration of dextromethorphan (DM). In addition to performingstandardized assessments using the Hamilton Depression Rating Scale(HAM-D), we evaluate two potential biomarkers of antidepressant efficacyto enable rapid future prediction of the onset of antidepressantactions: alterations in 1) voice parameters, and 2) corticospinalexcitability. The methods and formulations and compositions of thisinvention improves therapeutic outcomes for individuals with depression.

The present invention shows that fast acting antidepressant effects canbe achieved with tolerable side effects for translation into the generalclinical population. In addition, predictive biomarkers of the onset oftherapeutic actions are identified for quick and easy incorporation intostandard practice settings. The present invention shows:

1. Demonstrate that transbuccal administration of ketamine produces fastacting antidepressant effects: To minimize some of the problematic sideeffects associated with intravenous administration of ketamine, recentinvestigations have attempted alternate routes of ketamineadministration to elicit rapid antidepressant effects. Though theliterature regarding oral ketamine dosing for depression remains mixed,off-label use of transbuccal ketamine in a day-hospital setting atChestnut Ridge Center suggests that it can cause rapid antidepressanteffects that last for approximately two weeks. The current proposal willvalidate the dose and route of administration, and systematicallycharacterize the magnitude of the antidepressant effects and sideeffects, along with its time course.2. Compare the efficacy of oral dextromethorphan (DM) as a fast actingantidepressant drug relative to ketamine: DM, which is most commonlyused as a cough suppressant, shares many overlapping mechanisms ofaction with ketamine, but with a much more favorable safety profile.Therefore, we will determine whether similarly to ketamine, DM canproduce rapid antidepressant actions. To facilitate comparisons betweenthe two medications, Specific Aims 1 and 2 will be addressed using across-over design, with each patient serving as his or her own control.3. Identify biomarkers that predict antidepressant efficacy: Tocomplement HAM-D scores and provide additional validation ofantidepressant efficacy, we will evaluate two biomarkers that have beenpreviously shown to change with antidepressant therapy. In individualswho respond to antidepressant treatment, alterations in acoustic vocalparameters (eg. speech rate, voice frequency) and corticospinalexcitability (e.g. resting motor threshold) have been reported. Sinceboth of these measures can be easily and objectively quantified, we willevaluate the extent to which they predict responsiveness to treatment.Such tools will have value for identifying patients who are benefittingthe most from treatment. This study ultimately contributes to theidentification of fast acting antidepressant drugs that can be usedsafely and effectively by individuals suffering from depression.

This invention examines two strategies that are intended to evoke rapidantidepressant effects with more tolerable side effects than intravenousketamine: 1) transbuccal ketamine, and 2) oral DM. Both medications areFDA-approved for other indications making them amenable for repurposingand quick translation into clinical settings. Ketamine: Ketamine isFDA-approved as an anesthetic agent. However, off-label use of the drugcan elicit antidepressant effects within 24 hours of administration,with efficacy sustained for up to two weeks (i.e. rapid antidepressanteffect). The rapid antidepressant effects of ketamine are thought to beinitiated through its actions as an N-methyl-D-aspartate (NMDA) receptorantagonist, with the sustained effects of the drug resulting fromsynaptogesis and structural reorganization in the prefrontal cortex, acritical brain region that becomes compromised in depressions. Effortsthus far to overcome the side effect liabilities of ketamine havefocused on: 1) elucidating the mechanism(s) of the ketamine effects inan effort to identify or develop new compounds with better tolerability(e.g. compounds that target mechanisms downstream from the NMDAreceptor), and 2) utilizing alternate routes of administration anddosing to reduce the severity of the side effects. The first strategyhas stimulated exciting new avenues of research in drug discovery whichcould benefit patients in the future. We have chosen to focus on thelatter strategy which is likely to result in faster application intoclinical practice. Preliminary data for ketamine. Based on publishedreports that oral dosing with ketamine could provide antidepressanteffects in at least some patients, we have utilized this drug atChestnut Ridge Center in treatment resistant patients, who have notresponded to other antidepressant medications under conditions ofstandard off-label usage which is accepted in the profession. In thesesituations, patients are administered a 0.5 mg/kg dose of ketamine(which is a common dosage reported in the literature). In an effort toreduce side effects, liquid ketamine is placed on the tongue of thepatients and they are instructed to hold it in their mouths for as longas possible. Thus, in contrast to standard oral dosing, where the drugis simply swallowed, the route of administration used in this method ofthis invention in our patients is described as transbuccal. Thesepatients are generally seen daily for group therapy as part of ourday-hospital program. Antidepressant effects, which are assessed bypatient report and clinician observation, are generally seen within 24hours and last for two weeks (FIG. 1), after which another dose ofketamine needs to be administered to maintain/re-establish therapeuticeffects. No hallucinations, extreme sedation, euphoria, or other seriousside effects have been reported under these conditions. The pilot studyproposed herein will validate the efficacy of the transbuccal route ofketamine as a viable option for eliciting fast acting and sustainedantidepressant effects, with a side effect profile suitable for use inout-patients. Dextromethorphan (DM): In contrast to the use of ketaminewhich is highly controlled, DM is available over-the-counter as a coughsuppressant. It has been hypothesized to produce antidepressant actionsbased on overlapping mechanisms of action with ketamine, thoughpeer-reviewed data have yet to be published. DM has moderate affinityfor NMDA receptors, and is rapidly metabolized in the body todextrorphan, a compound that produces robust NMDA antagonist actionssimilar to ketamine. In addition, dextromethophan and ketamine both havesignificant affinity for sigma receptors which elicitsantidepressant/like actions in preclinical models and clinical trials,which may be of particular relevance for eliciting CNS structuraladaptations that contribute to rapid and sustained therapeutic effects.Preliminary studies for DM: In preclinical studies, we have recentlydemonstrated that DM produces antidepressant like effects. Similar toketamine and the tricyclic antidepressant drug imipramine, DM dosedependently reduces immobility time in the forced swim test, which isrecognized as the most established animal model for predicting clinicalantidepressant efficacy. These results suggest that similar to what hasbeen hypothesized by a number of investigators, DM can be expected toproduce antidepressant effects in humans. Biomarkers: Biomarkers arequantitative measurements that provide clinicians and researchersvaluable insight into the diagnosis, treatment, and prognosis ofpathological conditions. Since a significant challenge in treatingindividuals for depression is predicting who will respond/is respondingto a particular pharmacotherapy (which can take weeks to develop withconventional medications), the identification of biomarkers fortherapeutic responses to antidepressant treatment is invaluable. Thoughthis is less of an issue with fast acting antidepressant drugs whosetherapeutic effects are expected to appear within days of treatment,biomarker monitoring would still nonetheless be helpful for identifyingindividuals who are likely to benefit from a particular pharmacotherapy.Currently, the only objective, validated methods for determiningresponse to antidepressant treatment are the use of standardized scales,such as the HAM-D. These generally should be administered by a healthcare professional and are thus not practical for daily monitoring. Inthe present proposal, we focus on two potential biomarkers (i.e.alterations in speech parameters and resting motor threshold) that wouldbe relatively quick to administer and easy to incorporate into standardclinical practice. Speech parameters: Using commercially availablesoftware for detection of fundamental frequency and latency to respond,vocal prosody has been reported to have 79% accuracy in detectingdepression. Based on earlier literature as well as observations in theclinic, the parameters that we are most interested in monitoring arespeech rate and voice frequency variability because depressedindividuals tend to speak slower and with a flattened intonationcontour. These parameters can be easily measured from audio recordingsof patients reading a standard reading passage. In addition, pause timebetween words and latency to respond to a standardized question will bequantified. Tremor and short-term frequency perturbation (vocal jitter)from a sustained phonation of “ah” will also be measured as they areknown to increase in response to stress, a known risk factor fordepression. Corticospinal excitability: An increased resting motorthreshold in response to transcranial magnetic stimulation (TMS) hasbeen reported in patients who are responding to antidepressanttreatment, including electroconvulsive shock. This suggests that adecrease in corticospinal excitability may accompany rapidantidepressant effects that are produced by drugs, such as ketaminewhich has yet to be investigated. Innovation results from theidentification of fast acting antidepressant drugs with a favorable sideeffect profile that is amenable to quick translation into the generalclinical population. Moreover, validated biomarkers that are alsoamenable to rapid integration into normal clinical practice could assistin monitoring therapeutic outcomes in patients with depression. Approachan open-label, cross-over design will be used to assess the therapeuticefficacy of ketamine and DM in treatment resistant patients with majordepression. Fast acting antidepressant effects with tolerable sideeffects can be achieved using transbuccal ketamine administration and/ororal DM methods and compositions of this invention. Moreover, we expectthat the onset of antidepressant effects will be preceded by alterationsin vocal prosody and resting motor threshold responses. We discuss theresearch design including but not limited to such issues as: probabilityof group assignment, potential for subject to be randomized to placebogroup, use of control subjects, etc.

This is a pilot study to test the effect of Ketamine andDextromethorphan on mood in patients with treatment resistantdepression. Study will be conducted at Chestnut Ridge Center, DayHospital. We plan to recruit 10 patients in this pilot study which willbe a cross over study in which patient will act as their own control.Patients recruited will have an initial clinical interview and will beassessed for psychiatric psychopathology and medication trials that theyhave had. All patients will receive a Personality Assessment Inventory(PAI) All patients in study will have initial screen which is the HAM-Dprior to administration of any medication. Patients will then receive aone-time dose of 0.5 mg/kg of oral ketamine at Chestnut Ridge Centerwhich will be supervised and monitored by nursing staff. Patients willbe asked to keep in their mouth as long as they can to enhance oralabsorption of the medication. They will be requested to come the morningof receiving medications empty stomach. Patients will then continue withtheir routine group therapy at the Day Hospital at Chestnut Ridge Centerand during this time they will also be closely monitored for any adverseeffects of the medications. Patients will be assessed 5 days a week,while they attend group therapy at the day hospital. During thisassessment will assess for mood through repeat HAM-D and side effectsfrom the medication. At 2 weeks, will repeat same one time dosage of 0.5mg/kg of oral ketamine and continue to monitor for side effects and moodlike done previously. At the end of one month, patients will have across over to dextromethorphan. Patients will be getting one time doseof 2.7 mg/kg dextromethorphan. Patients will then continue with theirroutine group therapy at the Day Hospital at Chestnut Ridge Center andduring this time they will also be closely monitored for any adverseeffects of the medications. Patients will be assessed 5 days a week,while they attend group therapy at the day hospital. During thisassessment will assess for mood through repeat HAM-D and side effectsfrom the medication. Primary outcome measures:—HAM-D Secondary outcomemeasures:—TMS—Speech pathology assessment for rate and range of speech.

Specify inclusion criteria:

Age 19 years and older.—Patients with moderate to severe depression.

Specify exclusion criteria:

Patients with known liver disease.—Patients with life threateningmedical problems,—Currently medically unstable patients.—Pregnantwomen—Infants and children—Patients who lack medical decision makingcapacity.

Patient who would require medication adjustment during time in thestudy.

Patients will be monitored closely on a regular basis, 5 days a week inthe Day Hospital and Chestnut Ridge Center. Patient will be closelymonitored from symptoms immediately after administration of drug(ketamine/dextromethorphan). Patients will be seen 5 days a week inmedical rounds by staff psychiatrist and nursing staff and will beassessed for any side effects of medications. In case of any immediatelife threatening side effects patients that may arise patients will besent to Ruby Memorial Hospital for further evaluation and treatment.These patients will not be permitted to continue with study.

Patients who are enrolled in this study will have met the DSN-IVdiagnostic criteria for major depression and will be consideredtreatment resistant, making them well suited candidates for innovativetreatment options. They will be instructed to arrive on an empty stomachthe mornings they receive medication (i.e. no food after 9:00 p.m. theprevious night). In addition to receiving study medications, they willbe expected to participate in the day-hospital treatment program atChestnut Ridge Center which includes daily therapy sessions (whichrepresents standard care for these patients). Baseline measurements:Prior to initiating drug therapy with ketamine, baseline assessmentswill be performed for the following: 1) HAM-D, 2) standard readingpassage (for the measurement of voice parameters), and 3) TMS. The HAM-Dwill be performed by the M.D./Ph.D. student. It was chosen over otherdepression scales because it has been effective in detectingantidepressant effects of both ketamine and sigma receptor agonists. Forthe measurement of voice parameters, study participants will be recordedreading a standard reading passage (Rainbow Passage), producing asustained vocalization (“ah”), and responding to a standardizedquestion. The digital audio recordings will be analyzed using aComputerized Speech Lab (CSL, Model 4400; KayPentax, Lincoln Park, N.J.)system. The mean speech rate (syllables per second), response latency,and percent pause time will be determined using KayPentax Motor SpeechProfile (MSP Model 5141) software. The mean vocal fundamental frequency,tremor rate, frequency range, and frequency perturbation (vocal jitter)will be determined using KayPentax Multi-Dimensional Voice Profile (MDVPModel 5105) software. The determination of corticospinal excitabilitywill be made using single-pulse TMS of the primary motor cortex.Responses to TMS, motor evoked potentials, will be obtained from surfaceelectromyogram of the first dorsal interosseous muscle of the dominanthand. Resting motor threshold will be determined for each subject as thelowest TMS amplitude that causes motor evoked potentials larger than 50μV in 50% of trials when the arm is at rest. It should be emphasizedthat the TMS parameters used in this portion of the study will be wellbelow those used to elicit antidepressant effects on their own. Ketaminetrial: The first treatment arm will evaluate ketamine. Followingbaseline measurements, the subjects will be taken to a quiet, non-examroom for the next hour, where they will be given a one time dose of 0.5mg/kg of liquid ketamine and instructed by the nursing staff to hold itin their mouths for as long as possible to enhance absorption of themedication; they will be allowed to relax and will be unobtrusivelyobserved for potential side effects during this time. Subjects will thencontinue their routine group therapy as part of the day-hospital programat Chestnut Ridge and during which time they will continue to bemonitored by health care staff for adverse effects of the medication(e.g. extreme sedation and hallucinations which have been problematicafter intravenous dosing of ketamine; suicidal ideation after SSRIs).Subjects will be assessed five days a week as described for the baselinemeasurements using the HAM-D, voice recordings, and IMS, before theyattend group therapy at the day-hospital. Since earlier observations andreports indicate that the ketamine effects last for approximately twoweeks, at the start of the third week, the subjects will receive anotherone-time dose of 0.5 mg/kg liquid ketamine in order to establishreproducibility of the response for each subject. The monitoring anddata collection will occur as described for the initial two weeks oftreatment. At the end of one month (the second two-week period withketamine), the subjects will cross-over to testing with DM. DM trial:The second treatment arm will evaluate DM. For the purposes of thispilot study, all of the subjects will initially receive ketamine sincemuch more is known about the use of this drug as a fast actingantidepressant, providing a credible point of reference for comparisonsto DM, which we hope to be the first to report as an antidepressantdrug. For the initial evaluation, we will test a single oral dose of DM,2.7 mg/kg, which was selected because it roughly matches the subjectiveeffects produced by ketamine at its test dose of 0.5 mg/kg. Though thisdose of DM is slightly higher than its FDA-recommended dose for coughsuppression 120 mg/day, we do not anticipate problems with serious sideeffects because it is not unusual for individuals to take more than therecommended dose, with reports of abuse involving dosages measured ingrams. Similar to the ketamine arm of the trial, subjects will beclosely monitored for side effects, and evaluated using the HAM-D,standard reading passage, and TMS in association with their daily grouptherapy sessions five days a week as part of the day-hospital program atChestnut Ridge. Three possible outcomes are anticipated: 1) DM produceseffects comparable to ketamine, 2) DM produces transient therapeuticeffects, or 3) DM has no significant therapeutic effects. If therapeuticeffects are observed during the initial two-week evaluation of DM, thenat the start of the third week, a second one-time DM dose of 2.7 mg/kgwill be administered to evaluate the reproducibility of the effect. Iftransient or no therapeutic effects are observed during the initialtwo-week trial with DM, then the dose of DM administered at the start ofthe third week will be doubled to 5.4 mg/kg. Assessments will beperformed as described for the previous drug exposures.

Study participants are treatment resistant and not responding tocurrently available antidepressant drugs. Therefore, they may benefitfrom improved mood with the proposed study medication, with the effectsanticipated to occur much more rapidly than convention antidepressantdrugs. Subjects will also benefit from participation in group therapy aspart of the day hospital program at Chestnut Ridge Center.

The potential benefits of this research to society and thescientific/medical community is that fast acting antidepressanttreatments that are amenable to use in the general population may beidentified. Also, simple to use biomarkers to predict antidepressantefficacy may also be identified which can be readily implemented instandard clinical settings. Current antidepressant drugs take severalweeks before therapeutic benefits are achieved, and about 30% ofindividuals still do not respond. Heretofore, fast acting antidepressantdrugs that can be used in the general population are unavailable. Theidentification of such a composition and methods, as set forth in thisinvention transforms the treatment of depression in patients.

Treatment resistant depression is a leading cause of morbidity andmortality in the world. Many patients have tried multiple medicationswith minimal response. Ketamine and dextromethorphan are bothmedications that are well known with side effect profiles being wellstudied and monitored. Use of ketamine and dextromethorphan asantidepressants opens up a new avenue of hope in patients who have beenbattling with depression that have not responded to conventionaltreatment.

HUMAN SUBJECTS Protection of Human Subjects 1. Risk to Human Subjects

a. Human Subjects Involvement, Characteristics, and Design

-   -   We recruit 10 individuals, age 18 years and older, with        treatment resistant depression as subjects for this study.        Exclusion criteria include individuals with substance abuse,        cardiac disease or arrhythmia; individuals who require        adjustments of other medications during the time course of the        study; women who are pregnant or nursing; infants, children        under 18, and others who are unable to provide their own        consent. Existing medications that the subjects are taking will        not serve as exclusion criteria unless they have known drug-drug        interactions with the study medications, or if the doses will be        significantly altered during the course of the study; since the        patients are treatment resistant (i.e. failed to respond to at        least two conventional medication options), as long as their        current medications remain constant throughout the study and do        not interact with the study drugs, they should not affect the        outcome. All aspects of the study will be performed at the        Chestnut Ridge Center and the WVU Health Sciences Center by        trained personnel. The subjects will be administered drugs that        are anticipated to produce rapid antidepressant effects in an        open label cross over design, and participate in group therapy        sessions. They will also be administered the HAM-D scale,        recordings of them reading a standard reading passage (i.e.        Rainbow Passage¹) will be made, along with TMS measurements.        Subjects will have their corticospinal excitability measured        using TMS. TMS is a noninvasive, pain free way to stimulate the        human cortex. Single-pulse TMS is considered to have no        significant safety risks.² The text of the Rainbow Passage is as        follows: “When the sunlight strikes raindrops in the air, they        act like a prism and form a rainbow. The rainbow is a division        of white light into many beautiful colors. These take the shape        of a long round arch, with its path high above, and its two ends        apparently beyond the horizon. There is, according to legend, a        boiling pot of gold at one end. People look, but no one ever        finds it. When a man looks for something beyond his reach, his        friends say he is looking for the pot of gold at the end of the        rainbow.” Each patient will receive ketamine in the first        treatment arm and then dextromethorphan/quinidine in the second        treatment arm. This set up allows for easy comparisons between        the two treatments, as the first one is a known fast acting        antidepressant that will prime the patients to evaluate any        therapeutic benefits of a novel, potentially fast acting,        antidepressant.

b. Sources of Materials

-   -   The assessment of therapeutic response will be measured using        the HAM-D scale and clinical observations. Side effects (if any,        e.g. perceptual disturbances, confusion, elevated blood        pressure, elevated heart rate, sedation, and euphoria) will also        be noted. All collected data will be de-identified and assigned        a subject code for analysis. The data will be kept in locked        areas which can be accessed only by study personnel.

c. Potential Risks

-   -   The risks to the subjects for participation in the study are        low, relative to the risks associated with their depression        remaining untreated due to unresponsiveness to existing        antidepressant drugs (treatment resistant). Both study        medications, ketamine and dextromethorphan/quinidine, are        FDA-approved. Earlier reported side effects with intravenous        administration of sub-anesthetic doses of ketamine include:        perceptual disturbances, confusion, elevated blood pressure,        sedation, and a short lived “high”. No side effects (except for        a transient, mild headache and slight dizziness in one patient        each soon after administration) were observed in the patients in        the preliminary data (oral mucosa absorption of ketamine). The        efficacy of ketamine as a fast acting antidepressant drug has        been reported in the scientific literature using intravenous        administration; the proposed administration route is expected to        reduce many of the side effects associated with the intravenous        route of administration, with the dose chosen for this study        previously showing efficacy with off-label use at the study        site. Dextromethorphan/quinidine is available for the treatment        of pseudobulbar affect and is considered a safer alternative to        ketamine. The two doses of dextromethorphan/quindine proposed        for use meets the FDA- and EMA-approved oral doses for the        treatment of pseudobulbar affect, and were selected to provide        initial insights into its potential antidepressant efficacy. We        do not anticipate serious side effects with these doses.        Moreover, the drugs will be administered to study participants        one-hour prior to beginning their first day of group therapy at        Chestnut Ridge Center, where they will be under the observation        of health care professionals. They will return for daily group        therapy sessions for five days each week, providing ample        opportunity for them to be directly observed by health care        professionals for untoward side effects. In the unlikely event        that they require medical attention when not on site, they will        be provided cards containing the contact information for the        P.I.s and advised to have the emergency room or urgent care        provider notify them.

2. Adequacy of Protection Against Risks

a. Recruitment and Informed Consent

-   -   Subjects will be recruited through the Chestnut Ridge Center, or        through local advertisements if needed. Personnel affiliated        with the study will obtain informed consent from all study        participants. Informed consent involves an explanation of        possible risks and benefits of participating in the study, as        well as rights afforded to participants during the study.        Specifically, informed consent will contain the study procedure,        duration, possible risks and benefits, confidentiality,        researcher contact information, and other pertinent information        (e.g., the right to withdraw consent at any time) so that        participants can make an informed decision before participating.        Personnel will also be available to answer any questions the        participant may have about the study, or their rights and        responsibilities as a research participant. All forms and study        information that can be linked to a specific individual will        kept in a locked file cabinet at Chestnut Ridge Center that can        be accessed only by study personnel. Confidentiality will        further be maintained through the use of de-identified data for        analysis and reporting. Exclusion criteria include individuals        with substance abuse, cardiac disease or arrhythmia; individuals        who require adjustments of other medications during the time        course of the study; women who are pregnant or nursing; infants,        children under 18, and others who are unable to provide their        own consent.

b. Protections Against Risk

-   -   Although the potential risks of participation in these studies        are anticipated to be minimal, measures will be taken to further        protect against risk. Children 18 years of age and older will be        allowed to participate as they are capable of providing their        own informed consent and thus will receive the same protections        against risk as adults. Patients will undergo group therapy at        Chestnut Ridge Center five days each week of the study,        including the days that they receive study medications. If side        effects are observed, they will be expeditiously treated        on-site. If treatment in an emergency room or urgent care center        is needed when outside of the study environment, the subjects        will have cards containing the contact information for the P.I.s        and advised to have the care provider notify them. All adverse        events will be reported to an internal data safety and        monitoring board in the department and the IRB for review.        Furthermore, confidentiality will be carefully guarded at all        stages of participation. At no time will participants' names be        associated with any data provided. All materials will be stored        separately in locked filing cabinets that are only accessible to        the research team. These measures have been used successfully by        the team members in the past, and we expect that they will        continue to be effective at minimizing potential risks to        participants.

3. Benefits of the Research to Human Subjects and Others

Study participants are treatment resistant and not responding tocurrently available antidepressant drugs. Therefore, they may benefitfrom improved mood with the proposed study medication, with the effectsanticipated to occur much more rapidly than convention antidepressantdrugs. Subjects will also benefit from participation in group therapy aspart of the day hospital program at Chestnut Ridge Center. The benefitsof this invention to society and the scientific/medical community isthat fast acting antidepressant treatments of this invention areamenable to use in the general population. Also, simple to usebiomarkers to predict antidepressant efficacy may also be identifiedwhich can be implemented in standard clinical settings.

4. Importance of the Knowledge to be Gained

Current antidepressant drugs take several weeks before therapeuticbenefits are achieved, and about 30% of individuals still do notrespond.

5. Data and Safety Monitoring Plan

The compositions of this invention are administered to participantsone-hour prior to beginning group therapy at Chestnut Ridge Center,where they will be under continuous observation by health careprofessionals. They will return for daily group therapy sessions forfive days each week, for the next two weeks, providing ample opportunityfor them to be directly observed by health care professionals foruntoward side effects. In the unlikely event that subjects requiremedical attention when not on site, they will be provided cardscontaining the contact information for the P.I.s and advised to have theemergency room or urgent care provider notify them. Adverse eventsrelated to participation in the study will be reported to an internaldata safety and monitoring board in the Department of BehavioralMedicine and Psychiatry and IRB for review.

In one embodiment of the present invention, a method is provided oftreating depression disease in a patient comprising administering to amucosal membrane of a patient an effective amount of a compositioncomprising an effective amount of ketamine, wherein said mucosaladministration of said composition allows for the transmucosalabsorption of the composition into the patient's blood stream therebyeliminating the digestive tract of said patient for providing a rapidacting antidepressant effect for treating depression in the patient.This method includes including administering said composition to saidmucosal membrane of said patient over a time period from one millisecondto ten minutes, and preferably over a time period that is from onesecond to three minutes. This method includes providing said compositioncontained within a dosage form capable of being administered to themucosa of said patient or to the mucosal membrane of said patient.Preferably this method includes providing wherein said dosage form is aliquid, gel, powder. More preferably, this method includes providingsaid dosage form that is in the form of a pharmaceutically acceptabletroche, film, capsule, tablet, particle, solution, suspension, lollipop,lozenge, emulsion, spray, or aerosol. This method includes providing aneffective amount of said ketamine that is 0.5 mg per kilogram of apatient's body mass. The method includes administering said compositionto said mucosal membrane that is in an oral cavity of said patient.Preferably, the method includes administering said composition to abuccal cavity of said oral cavity of said patient. This method includes,for example, wherein said depression is selected from the group ofunipolar depression disease, bipolar depression disease, and depressiontreatment resistant disease. An optional embodiment of this methodincludes wherein said administration of said ketamine is followed byadministering to said patient an effective amount of a compositioncomprising an effective amount of dextromethorphan, and preferablyadministering said composition comprising dextromethorphan in within aclinically effective time period from the administration of saidcomposition comprising ketamine, and more preferably administering saidcomposition comprising dextromethorphan within ninety days from theadministration of said composition comprising ketamine.

In another embodiment of this invention, a pharmaceutically acceptablecomposition is provided comprising an effective amount of ketamine,wherein said ketamine is distributed within a pharmaceuticallyacceptable vehicle, wherein said vehicle is capable of being placed incontact with a mucosal membrane of a patient. The pharmaceuticallyacceptable composition and said vehicle are capable of delivery to anoral cavity of said patient. Preferably, said composition and saidvehicle are capable of delivery to a buccal cavity of the oral cavity ofsaid patient. The pharmaceutically acceptable composition includeswherein said composition has a dosage form that is a liquid, gel, orpowder. More preferably, the pharmaceutically acceptable composition ofthis invention is a dosage form of a pharmaceutically acceptable troche,film, capsule, tablet, particle, solution, suspension, lollipop,lozenge, emulsion, spray, or aerosol. Most preferably, thepharmaceutically acceptable composition of this invention includeswherein said effective amount of said ketamine is 0.5 mg per kilogram ofa patient's body mass.

Another embodiment of this invention provides a pharmaceuticallyacceptable composition comprising an effective amount of ketamine,wherein said ketamine is distributed within a pharmaceuticallyacceptable vehicle, wherein said vehicle is capable of being placed incontact with a mucosal membrane of a patient, and wherein thepharmaceutically acceptable vehicle is a device having a mucoadhesivelayer containing said ketamine buffered to a pH of between about 4.0 and7.0, and a non-adhesive backing layer buffered to a pH of between 4.0and 6.0 wherein the pH of the mucoadhesive layer and the non-adhesivebacking layer are different wherein the mucoadhesive layer and thenon-adhesive backing layer comprise different combinations of polymersbut each layer comprises at least one water-erodible polymer selectedfrom the group of cellulosic polymers, olefinic polymers, polyethers,and polyalcohols, wherein following transmucosal administrationexcessive exposure to ketamine is avoided. Most preferably, the amountof ketamine contained within said mucoadhesive layer is 0.5 mg perkilogram of a patient's body mass. Preferably, the water-erodiblepolymer is selected from the group consisting of polyacrylic acid,sodium carboxymethylcellulose, hydroxyethyl cellulose,hydroxyethylmethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide,and ethylene oxide-propylene oxide co-polymers. The device may be in theform of a transmucosal buccal tablet, buccal film, and the like. Thosepersons skilled in the art understand that any number of bufferingagents may be included in the mucoadhesive layer with said ketamine foruse in buffering the pH of ketamine, wherein such buffering agentsinclude, but are not limited to for example, phosphates, phosphatesmonobasic, phosphates dibasic, phosphates tribasic, bicarbonates,acetates, and combinations thereof. The non-adhesive backing layer maybe further modified to control the erodibility of the layer by coatingthe non-adhesive backing layer with a hydrophobic polymer such as forexample but not limited to ethyl cellulose, cellulose acetate phthalate,and hydroxyl propyl methyl cellulose phthalate, provided that thenon-adhesive backing layer erodes in a moist environment of the oralcavity. Dissolution characteristics of the mucoadhesive layer and thebioavailability of ketamine may be adjusted accordingly depending uponthe water-erodible polymer employed in the formulation of the device.

Another embodiment of this invention provides a biomarker foridentifying a depression disease in a patient. The biomarker of thisinvention comprises predicting responsiveness to treating a patient byadministration to said patient a pharmaceutically acceptable compositionof ketamine, or dextromethorphan, or a combination of ketamine anddextromethorphan, and evaluating a change in alterations in acousticvocal parameters comprising speech rate and voice frequency, andalterations in corticospinal excitability comprising resting motorthreshold, in a patient at baseline prior to treatment and aftertreatment of said patient.

In yet another embodiment of this invention, a method of treatingdepression disease in a patient is provided comprising administeringorally or to a mucosal membrane of a patient an effective amount of acomposition comprising an effective amount of dextromethorphan, whereinsaid mucosal administration of said composition allows for thetransmucosal absorption of the composition into the patient's bloodstream thereby eliminating the digestive tract of said patient forproviding a rapid acting antidepressant effect for treating depressionin the patient. This method includes administering said composition tosaid mucosal membrane of said patient over a time period from onemillisecond to ten minutes, and preferably over a time period that isfrom one second to three minutes. This method includes wherein saidcomposition is contained within a dosage form capable of beingadministered to the mucosa of said patient or to the mucosal membrane ofsaid patient. Preferably, this method includes providing said dosageform that is a liquid, gel, powder. More preferably, this methodincludes providing said dosage form that is in the form of apharmaceutically acceptable troche, film, capsule, tablet, particle,solution, suspension, lollipop, lozenge, emulsion, spray, or aerosol.This method includes administering said composition to said mucosalmembrane that is in an oral cavity of said patient. Preferably, thismethod includes administering said composition to a buccal cavity ofsaid oral cavity of said patient. This method includes wherein thedepression is selected from the group of unipolar depression disease,bipolar depression disease, and depression treatment resistant disease.This method optionally includes wherein said oral administrationincludes swallowing said composition comprising dextromethorphan.

Another embodiment of this invention provides a pharmaceuticallyacceptable composition comprising an effective amount ofdextromethorphan, wherein said dextromethorphan is distributed within apharmaceutically acceptable vehicle, wherein said vehicle is capable ofbeing placed in contact with a mucosal membrane of a patient. Thepharmaceutically acceptable composition includes wherein saidcomposition and said vehicle are capable of delivery to an oral cavityof said patient, and preferably wherein said composition and saidvehicle are capable of delivery to a buccal cavity of the oral cavity ofsaid patient. The pharmaceutically acceptable composition of includeswherein said composition has a dosage form that is a liquid, gel, orpowder, and preferably the pharmaceutically acceptable composition is adosage form of a pharmaceutically acceptable troche, film, capsule,tablet, particle, solution, suspension, lollipop, lozenge, emulsion,spray, or aerosol. The pharmaceutically acceptable composition includeswherein said effective amount of said dextromethorphan is from 0.5 mg to2000.0 mg per dosage form.

Another embodiment of this invention provides a pharmaceuticallyacceptable composition comprising an effective amount ofdextromethorphan, wherein said dextromethorphan is distributed within apharmaceutically acceptable vehicle, wherein said vehicle is capable ofbeing placed in contact with a mucosal membrane of a patient, andwherein the pharmaceutically acceptable vehicle is a device having amucoadhesive layer containing said dextromethorphan buffered to a pH ofbetween about 4.0 and 7.0, and a non-adhesive backing layer buffered toa pH of between 4.0 and 6.0 wherein the pH of the mucoadhesive layer andthe non-adhesive backing layer are different and wherein themucoadhesive layer and the non-adhesive backing layer comprise differentcombinations of polymers but each layer comprises at least onewater-erodible polymer selected from the group of cellulosic polymers,olefinic polymers, polyethers, and polyalcohols, wherein followingtransmucosal administration excessive exposure to dextromethorphan isavoided. Most preferably, the amount of dextromethorphan containedwithin said mucoadhesive layer is from 0.5 mg to 2000.0 mg per dosageform. Preferably, the water-erodible polymer is selected from the groupconsisting of polyacrylic acid, sodium carboxymethylcellulose,hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethyleneglycol, polyethylene oxide, and ethylene oxide-propylene oxideco-polymers. The device may be in the form of a transmucosal buccaltablet, buccal film, and the like. Those persons skilled in the artunderstand that any number of buffering agents may be included in themucoadhesive layer with said dextromethorphan for use in buffering thepH of dextromethorphan, wherein such buffering agents include, but arenot limited to for example, phosphates, phosphates monobasic, phosphatesdibasic, phosphates tribasic, bicarbonates, acetates, and combinationsthereof. The non-adhesive backing layer may be further modified tocontrol the erodibility of the layer by coating the non-adhesive backinglayer with a hydrophobic polymer such as for example but not limited toethyl cellulose, cellulose acetate phthalate, and hydroxyl propyl methylcellulose phthalate, provided that the non-adhesive backing layer erodesin a moist environment of the oral cavity. Dissolution characteristicsof the mucoadhesive layer and the bioavailability of dextromethorphanmay be adjusted accordingly depending upon the water-erodible polymeremployed in the formulation of the device.

In another embodiment of this invention, a method is provided oftreating depression disease in a patient comprising administering to apatient an effective amount of a composition comprising an effectiveamount of dextromethorphan via the oral route of said patient forproviding a rapid acting antidepressant effect for treating depressionin the patient.

It will be appreciated that the method and rapid acting pharmaceuticallyacceptable compositions of this invention are effective treatment ofdepression in treatment resistant patients. These inventions change theworld of antidepressant pharmacotherapy as they grant to these patientsantidepressant therapy within 24 hours of treatment and in turn decreasethe morbidity associated with depressive illness.

REFERENCES

¹ Fairbanks G. The rainbow passage. In: Voice and Articulation Drillbook(2nd ed). New York: Harper & Row; 1960; 127.² Groppa S, Oliviero A, Eisen A, Quartarone A, Cohen L G, Mall V,Kaelin-Lang A, Mima T, Rossi S, Thickbroom G W, Rossini P M, Ziemann U,Valls-Solé J, Siebner H R. A practical guide to diagnostic transcranialmagnetic stimulation: Report of an IFCN committee. Clin Neurophysiol.2012 May; 123(5):858-882.Jick H, Kaye J A, Jick S S. Antidepressants and risk of suicidalbehaviors. JAMA 2004; 292 (3): 338-43.Rot M A, Collins K A, Murrough J W. Safety and efficacy of repeated lowdose intravenous ketamine for treatment-resistant depression. BiolPsychiatry 2010; 67: 139-145.Papp M, Moryl E. Antidepressant activity of non-competitive NMDAreceptor antagonists in a chronic mild stress model of depression. EUR JPharmacol. 1994; 263 (1-2): 1-7.Zarate C A, Singh J B, Carlson P J. A randomized trial of anN-methyl-D-aspartate antagonist in treatment-resistant major depression.Arch Gen Psychiatry 2006; 63 (8) 856-864.

What is claimed is:
 1. A method of treating depression disease in atreatment resistant patient consisting of: administering to a mucosalmembrane of a patient an effective amount of a composition consisting ofan effective amount of ketamine or dextromethorphan, wherein saidmucosal administration of said composition allows for the transmucosalabsorption of said ketamine or said dextromethorphan into the patient'ssystemic blood stream and avoiding the first pass elimination of saidketamine or said dextromethorphan from the patient's digestive tract andliver for providing a rapid acting antidepressant effect for treatingdepression in a treatment resistant patient.
 2. The method of claim 1including administering said composition to said mucosal membrane ofsaid patient over a time period from one millisecond to ten minutes. 3.The method of claim 2 including wherein said time period is from onesecond to three minutes.
 4. The method of claim 1 including wherein saidcomposition is contained within a dosage form capable of beingadministered to the mucosa of said patient or to the mucosal membrane ofsaid patient.
 5. The method of claim 4 including wherein said dosageform is a liquid, gel, powder.
 6. The method of claim 4 includingwherein said dosage form is in the form of a pharmaceutically acceptabletroche, film, capsule, tablet, particle, solution, suspension, lollipop,lozenge, emulsion, spray, or aerosol.
 7. The method of claim 1 includingwherein said effective amount of said ketamine is 0.5 mg per kilogram ofa patient's body mass.
 8. The method of claim 1 including administeringsaid composition to said mucosal membrane that is in an oral cavity ofsaid patient.
 9. The method of claim 8 including administering saidcomposition to a buccal cavity of said oral cavity of said patient. 10.The method of claim 4 including administering said composition to saidmucosal membrane that is of a respiratory tract, a genitourinary tract,or rectal tract of said patient, and wherein said dosage form is in theform of a pharmaceutically acceptable troche, film, capsule, tablet,particle, solution, suspension, lollipop, lozenge, emulsion, spray, oraerosol.
 11. A pharmaceutically acceptable composition comprising: aneffective amount of ketamine or dextromethorphan, or both ketamine anddextromethorphan, wherein said ketamine or said dextromethorphan, orboth are distributed within a pharmaceutically acceptable vehicle,wherein said vehicle is capable of being placed in contact with amucosal membrane of a patient.
 12. The pharmaceutically acceptablecomposition of claim 11 wherein said composition and said vehicle arecapable of delivery to a mucosal membrane of a respiratory tract, agenitourinary tract, an oral tract, or rectal tract of said patient. 13.The pharmaceutically acceptable composition of claim 11 wherein saidcomposition and said vehicle are capable of delivery to an oral cavityof said patient.
 14. The pharmaceutically acceptable composition ofclaim 11 including wherein said composition has a dosage form that is aliquid, gel, or powder.
 15. The pharmaceutically acceptable compositionof claim 11 that is a dosage form of a pharmaceutically acceptabletroche, film, capsule, tablet, particle, solution, suspension, lollipop,lozenge, emulsion, spray, or aerosol.
 16. The pharmaceuticallyacceptable composition of claim 11 including wherein said effectiveamount of said dextromethorphan is 0.5 mg to 2000.0 mg per dosage form,and wherein said effective amount of said ketamine is approximately 0.5mg per kilogram of a patient's body mass per dosage form.
 17. Thepharmaceutically acceptable composition of claim 11 wherein saidpharmaceutically acceptable vehicle is a device having a mucoadhesivelayer containing said ketamine buffered to a pH of between about 4.0 and7.0, and a non-adhesive backing layer buffered to a pH of between 4.0and 6.0 wherein the pH of said mucoadhesive layer and said pH of saidnon-adhesive backing layer are different, wherein said mucoadhesivelayer and said non-adhesive backing layer comprise differentcombinations of polymers but each of said mucoadhesive layer and saidnon-adhesive backing layer comprise at least one water-erodible polymer.18. The pharmaceutically acceptable composition of claim 17 includingwherein said water-erodible polymer is one selected from the groupconsisting of a cellulosic polymer, an olefinic polymer, a polyether,and a polyalcohol.
 19. The pharmaceutically acceptable composition ofclaim 17 wherein said water-erodible polymer is at least one selectedfrom the group consisting of a polyacrylic acid, a sodiumcarboxymethylcellulose, a hydroxyethyl cellulose, a hydroxyethylmethylcellulose, a hydroxyethyl cellulose, a hydroxypropyl cellulose, apolyvinyl alcohol, a polyethylene glycol, a polyethylene oxide, and anethylene oxide-propylene oxide co-polymer.
 20. The pharmaceuticallyacceptable composition of claim 17 wherein said device is in the form ofa transmucosal buccal tablet or buccal film.
 21. The pharmaceuticallyacceptable composition of claim 17 including at least one bufferingagent contained in said mucoadhesive layer for use in buffering the pHof ketamine or dextromethorphan, or both ketamine and dextromethorphan.22. The pharmaceutically acceptable composition of claim 21 wherein saidbuffering agent is one selected from the group consisting of phosphates,phosphates monobasic, phosphates dibasic, phosphates tribasic,bicarbonates, acetates, and combinations thereof.
 23. Thepharmaceutically acceptable composition of claim 17 including ahydrophobic polymer for coating said non-adhesive backing layer forcontrolling the erodibility of said non-adhesive backing layer.
 24. Abiomarker for identifying depressive disease in a patient comprisingpredicting responsiveness to treating a patient by administration tosaid patient of a pharmaceutically acceptable composition of ketamine,or dextromethorphan, or a combination of ketamine and dextromethorphan,and evaluating a change in alterations in acoustic vocal parameterscomprising speech rate and voice frequency, and alterations incorticospinal excitability comprising resting motor threshold, in apatient at baseline prior to treatment and after treatment of saidpatient.
 25. A method of treating depression disease in a treatmentresistant patient consisting of: administering to a treatment resistantpatient an effective amount of a composition consisting of an effectiveamount of dextromethorphan to a mucosal membrane of said patient, sadcomposition provides transmucosal absorption of said dextromethorphaninto said patient's systemic bloodstream thereby avoiding the first-passelimination of said dextromethorphan from said patient's digestive tractand liver for providing a twenty-four hour rapid acting antidepressanteffect for treating depression in a treatment resistant patient.
 26. Themethod of claim 25 including wherein said mucosal membrane is of arespiratory tract, a genitourinary tract, an oral tract, or rectal tractof said patient.
 27. The method of claim 25 whereon said composition iscontained within a dosage form capable of being administered to themucosa of said patient or to the mucosal membrane of said patient. 28.The method of claim 27 including wherein said dosage form is in the formof a pharmaceutically acceptable troche, film, capsule, tablet,particle, solution, suspension, lollipop, lozenge, emulsion, spray, oraerosol.